Aspects for development of novel antibacterial medicines using a vitamin D3 decomposition product in Helicobacter pylori infection.

A previous study by our group demonstrated that a vitamin D3 decomposition product (VDP1) acts as the selective bactericidal substance on Helicobacter pylori. VDP1 is an indene compound modified with a carbonyl and an alkyl. The alkyl of VDP1 turned out to be a mandatory structure to exert effective bactericidal action on H. pylori. Meanwhile, it still remains to be clarified as to how influence the alteration of the carbonyl in VDP1 has on the anti-H. pylori activity. In this study, we synthesized novel VDP1 derivatives that replaced the carbonyl of VDP1 by various functional groups and investigated the antibacterial action of the VDP1 derivatives on H. pylori. VDP1 derivatives retaining either a hydroxy (VD3-1) or an acetic ester (VD3-3) exhibited more effective bactericidal action to H. pylori than VDP1. The replacement of the carbonyl of VDP1 by either an allyl acetate (VD3-2) or an acrylic acid (VD3-5) provided almost no change to the anti-H. pylori activity. Apart from this, an isomer of VDP1 (VD3-4) slightly improved anti-H. pylori activity of VDP1. Meanwhile, the replacement of the carbonyl of VDP1 by a methyl acrylate (VD3-6) attenuated the anti-H. pylori activity. As with VDP1, its derivatives also were suggested to exert the anti-H. pylori action through the interaction with myristic acid side chains of dimyristoyl-phosphatidylethanolamine, a characteristic membrane lipid constituent of this pathogen. These results indicate that it is capable of developing specific antibacterial medicines for H. pylori targeting the biomembranal dimyristoyl-phosphatidylethanolamine using VDP1 as the fundamental structure.

Indene Compounds Synthetically Derived from Vitamin D Have Selective Antibacterial Action on Helicobacter pylori.

Helicobacter pylori infects the human stomach and is closely linked with the development of gastric cancer. When detected, this pathogen can be eradicated from the human stomach using wide-spectrum antibiotics. However, year by year, H. pylori strains resistant to the antibacterial action of antibiotics have been increasing. The development of new antibacterial substances effective against drug-resistant H. pylori is urgently required. Our group has recently identified extremely selective bactericidal effects against H. pylori in (1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one (VDP1) (otherwise known as Grundmann's ketone), an indene compound derived from the decomposition of vitamin D3 and proposed the antibacterial mechanism whereby VDP1 induces the bacteriolysis by interacting at least with PtdEtn (dimyristoyl-phosphatidylethanolamine [di-14:0 PtdEtn]) retaining two 14:0 fatty acids of the membrane lipid constituents. In this study, we synthesized new indene compounds ((1R,3aR,7aR)-1-((2R,E)-5,6-dimethylhept-3-en-2-yl)-7a-methyloctahydro-4H-inden-4-one [VD2-1], (1R,3aR,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyloctahydro-1H-inden-4-ol [VD2-2], and (1R,3aR,7aR)-7a-methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-4-ol [VD3-1]) using either vitamin D2 or vitamin D3 as materials. VD2-1 and VD3-1 selectively disrupted the di-14:0 PtdEtn vesicles without destructing the vesicles of PtdEtn (dipalmitoyl-phosphatidylethanolamine) retaining two 16:0 fatty acids. In contrast, VD2-2, an indene compound lacking an alkyl group, had no influence on the structural stability of both PtdEtn vesicles. In addition, VD2-1 and VD3-1 exerted extremely selective bactericidal action against H. pylori without affecting the viability of commonplace bacteria. Meanwhile, VD2-2 almost forfeited the bactericidal effects on H. pylori. These results suggest that the alkyl group of the indene compounds has a crucial conformation to interact with di-14:0 PtdEtn of H. pylori membrane lipid constituents whereby the bacteriolysis is ultimately induced.